Lab Anim Res.  2011 Jun;27(2):133-140. 10.5625/lar.2011.27.2.133.

Granulocyte-Derived Cationic Peptide Enhances Homing and Engraftment of Bone Marrow Stem Cells after Transplantation

• Lee H
• Che JH
• Lee JC
• Chung SS
• Jung HS
• Park KS

• KMID: 2053662
• DOI: http://doi.org/10.5625/lar.2011.27.2.133

Abstract

Current strategies to accelerate hematopoietic reconstitution after transplantation include transplantation of greater numbers of hematopoietic stem/progenitor cells (HSPCs) or ex vivo expansion of harvested HSPCs before transplant. However, the number of cells available for transplantation is usually low, and strategies to expand HSPCs and maintain equivalent engraftment capability ex vivo are limited. We noted that activated granulocyte-derived cationic peptides positively primed responsiveness of HSPCs to a CXCL12 gradient. Accordingly, we noted that accelerated homing/engraftment of beta-defensin-2, a well-known antimicrobial cationic peptide, primed bone marrow nucleated cells (BMNCs) compared to normal BMNCs after transplantation into lethally irradiated recipients. We envision that small cationic peptides, which primarily possess antimicrobial functions and are harmless to mammalian cells, could be applied to prime HSPCs before transplantation. This novel approach would be particularly important in cord blood transplantation, where the number of HSPCs available for transplantation is usually limited.

Keyword

Cationic peptide; defensin-2; hematopoietic stem cells; transplantation; homing and engraftment

MeSH Terms

Bone Marrow
Fetal Blood
Hematopoietic Stem Cells
Peptides
Stem Cells
Transplants
Peptides

Figure

• 

  Figure 1 Migration of BMNCs and CFU-GM progenitor cells to a CXCL12 gradient. CXCL12 directly chemoattracts CFU-GM progenitor cells as well as BMNCs. Migration of BMNCs (A) and CFU-GM progenitor cells (B). Values are the fold increase of migrated cell numbers compared to media alone control. CXCL12 (ng/mL). *P<0.05 as compared with media alone control. The data shown represent the combined results from three independent experiments carried out in duplicate per group (n=6).

• 

  Figure 2 The cationic peptide hBD-2 enhances responsiveness of BM cells to a CXCL12 gradient. The migration of hBD-2-exposed BMNCs was significantly enhanced compared to that of normal BMNCs (A, BMNCs; B, CFU-GM progenitors) in response to a CXCL12 gradient. However, hBD-2 itself did not show direct chemotactic effect to BMNCs (C) and CFU-GM progenitor cells (D). Values are the fold increase of migrated cell numbers compared to control. CXCL12 (ng/mL), hBD-2 (µg/mL). *P<0.05 as compared to CXCL12 (50 ng/mL, A and B) or media alone control (C and D). The data shown represent the combined results from three independent experiments carried out in triplicate per group (n=9).

• 

  Figure 3 hBD-2 enhances p42/44 MAPK phosphorylation mediated by CXCL12. Downstream signaling mediated by the CXCL12-CXCR4 axis was strongly enhanced when CXCL12 was employed together with hBD-2 (A). hBD-2-primed CFU-GM progenitor cells showed enhance adhesion onto stromal cells (B). CXCL12 (L, 50 ng/mL; H, 300 ng/mL), hBD-2 (1 µg/mL). *P<0.05 as compared to non-primed CFU-GM progenitor cells. The data shown represent the combined results from three independent experiments carried out in duplicate per group (n=6).

• 

  Figure 4 hBD-2 exposure on BMNCs does not affect the viability and differentiation potential of BM-derived HSPCs. BMNCs were exposed to different doses of hBD-2 for 60 minutes at 37℃ before the colony forming assay. CFU-GM (A) and CFU-M (B) differentiation of BMNCs. No significant differences were observed between normal or hBD-2 primed BMNCs. The data shown represent the combined results from two independent experiments carried out in duplicate per group (n=4).

• 

  Figure 5 New strategy for the optimization of HSPC transplantation efficiency by employing cationic peptides. The homing and engraftment of BM-derived HSPCs (BM-HSPCs) and umbilical cord blood-derived HSPCs (UCB-HSPCs) might be accelerated by employing cationic peptides (i.e., hBD-2) as priming reagents. Mobilized or cationic peptide-primed HSPCs might home and engraft faster than BM-HSPCs or UCB-HSPCs. This novel approach would be particularly important in umbilical cord blood transplantation, where the number of HSPCs available for reconstitution of recipient is often limited.

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